Advanced therapy medicinal products in China: Regulation and development

Abstract Advanced therapy medicinal products (ATMPs) have shown dramatic efficacy in addressing serious diseases over the past decade. With the acceleration and deepening of China's drug regulatory reforms, the country sees a continuous introduction of policies that encourage drug innovation. The capacity and efficiency of the Center for Drug Evaluation (CDE), National Medical Products Administration have significantly improved, where substantial resources have been allocated to ATMPs with major innovations and outstanding clinical values that satisfy urgent clinical needs. These changes have greatly stimulated the research and development of biological products in China, ushering in a period of explosive growth in the number of investigational new drug (IND) applications of ATMPs. Here, we described China's ATMP regulatory framework and analyzed data on IND applications for ATMPs submitted to CDE. The data show that China's ATMP industry is expanding dramatically, but lagging behind in terms of the innovative targets and the coverage of indications. However, in recent years, the diversity of product types, targets, and indications is growing. We discussed challenges and opportunities in ATMP regulation. Risk‐based regulation and cross‐discipline collaborations are encouraged to promote more ATMPs toward market authorization in China.


INTRODUCTION
Advanced therapy medicinal products (ATMPs) are medicines based on genes and cells, including gene therapy products, cell therapy medicinal products, tissue engineered products and other types of products, which are characterized by complex biological features and manufacturing processes. 1 Generally, ATMPs are used to Up to August, 2022, there are 8 chimeric antigen receptor-T cell (CAR-T) products and 7 Adeno-Associate Virus (AAV) products approved on market globally, representing the majority of marketed ATMPs worldwide. Multiple ATMPs initiated pivotal clinical study and hopefully more CAR-T and other types of products will be approved in the next decade. 3 In China, National Medical Products Administration (NMPA) regulates ATMP as "innovative biological products" as defined in the Provisions for Drug Registration (NMPA Order No.27, 2020). In 2021, NMPA approved 2 CAR-T products on market, namely Axicabtagene Ciloleucel Injection and Relmacabtagene Autoleucel Injection. Their indications include relapse/refractory diffuse large B cell lumphoma and follicular lymphoma. By the end of 2022, the new drug application (NDA) filings of 4 CAR-T products have been accomplished and more ATMPs are predicted to submit NDA in the next following years.
Different from traditional biologicals, ATMPs have brought many new challenges to drug development and regulation in terms of development strategies, technical guidances and regulatory policies. At present, regulatory authorities in various countries and regions have issued many supportive policies and guidances. Within European Medicines Agency and US Food and Drug Administration (US FDA), expedited regulatory pathways were created that could possibly benefit ATMP companies, such as Regenerative Medicine Advanced Therapy in US and Priority Medicines scheme (PRIME) in EU. [4][5][6] New meeting modality has been created to improve the effective communications between regulators and stakeholders, such as the Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) in US FDA CBER. And many drug regulatory agencies worldwide have issued numerous product-specific technical guidances, describing the regulators' opinion and recommendations on ATMP development. 7 Here we introduce the current ATMP development status and regulatory scenario in China, which mainly focus on the optimization of drug review process and the analysis of investigational new drug (IND) applications of ATMPs. And, we discuss how NMPA improves the regulatory framework to address the challenges and accelerate ATMPs toward clinic.

THE REVIEW PROCESS AND REGULATORY FRAMEWORK OF ATMPS IN CHINA
With the deepening of regulatory reforms since 2015, the optimization of drug review process with multiple expedited programs cleared many obstacles hindering the development of ATMPs.

The expedited regulatory programs speed up the approval of ATMPs
To encourage innovative drug development, NMPA accelerates review and approval of ATMPs through multiple expedited programs such as Priority Review Pathway, Breakthrough Therapy Designation, Conditional Approval Pathway ( Figure 1). These programs remarkably reduced the time for NDA approval by prioritizing inspection, rolling review, more frequent meetings, etc. Up to November, 2022, a total of 6 CAR-T products were granted Priority Review Pathway, eight CAR-T products and two AAV products were granted Breakthrough Therapy Designation during the clinical trial stage, of which two CAR-T products were conditionally approved on market in 2021.

2.2
The drug review process is improved

Effective meetings facilitate communications
Since 2018, pre-IND meeting is suggested prior to IND submission to determine whether the data support clinical trial ( Figure 1). Large numbers of ATMP pre-IND and prepre-IND meetings have been applied, and drug reviewers have been involved in the early developmental stage of ATMPs. The data in ATMP IND files were assessed, and reviewer's feedback help stakeholders improve the master files, resulting in the markedly decrease of IND rejection rate. Meanwhile, advisory committee meetings have been held during review process if needed, to reach convergence between scientists, stakeholders, and regulators ( Figure 1).

F I G U R E 1
The workflow of Advanced therapy medicinal product (ATMP) review process with expedited programs and formal regulatory meetings. The ATMP development and review process include chemistry, manufacturing and control (CMC) and preclinical study, investigational new drug (IND) review, clinical trial implementation, new drug application (NDA) review, market authorization and post-approval study. Priority review pathway, breakthrough therapy designation and conditional approval pathway are three expedited programs that are commonly used in ATMP regulation. The formal regulatory meetings include pre-IND meeting and pre-NDA meeting, and in-review communication or advisory meeting may be held if necessary.

The regulatory framework of ATMPs is developed
In addition to the existing guidance on biological products, Center for Drug Evaluation (CDE) has issued a series of technical guidance documents describing current thinking on the development of ATMPs. These guidance documents clarified the definitions of each category of ATMPs in China and articulated the regulatory considerations of chemistry, manufacturing and control (CMC), nonclinical and clinical research with regard to the products ranging from immune cell therapy, in vivo gene therapy, ex vivo gene therapy, oncolytic viruses to gene editing and stem cell products (Table 1). Risk-based compliance is recommended, and communication with regulators is encouraged in these documents.

International collaboration promotes regulatory convergence
China's joining the International Conference on Harmonization (ICH) in 2017 paved a way for international collaboration in ATMP regulation. In 2020 ICH management committee meeting, NMPA proposed two reflection papers on the regulation of stem cell-based products and gene therapy products. Now CDE experts are enrolled in the ICH discussion of viral safety evaluation (ICH Q5A) and nonclinical biodistribution considerations (ICH S12) for gene therapy products.

ATMP IND application
The data on IND applications for ATMPs that were submitted to NMPA from January Identify the types of cellular therapy products which can be regulated as "biological products." Guidance for research and quality control of human gene therapy products 10 Clarifies the definition and categories of gene therapy products, in vivo products and ex vivo products. Describes the general technical requirements of CMC, nonclinical, and clinical.
Risk assessments are essential to ensure the safety of gene therapy products. Regulatory flexibility is recommended.
Guidance for research and quality control of human somatic cell therapy products 11 Provides the definition and categories of somatic cell therapy products. Describes the general technical requirements of CMC, nonclinical, and clinical.
Clarifies the technical requirements of raw materials, including human serum and human blood derivatives.

CMC
Guidance for CMC research and evaluation of in vivo gene therapy products 12 Provides the categories of in vivo gene therapy products.
Describes the detailed CMC technical requirements, including raw materials, manufacture, quality control, etc.
Indicates the risk-based CMC study strategy. Illustrate the product-specific technical requirements, including vector-based products, nucleic acid products, etc.
Guidance for CMC research and evaluation of gene manipulation system used to manufacture ex vivo gene therapy products 13 Provides the categories of gene manipulation systems used to make ex vivo gene therapy products. Describes the detailed CMC technical requirements. Clarifies the risk-based requirements for the gene editing tools in different using scenarios.
Introduces various types of gene editing tools, including the viral vectors, nonviral vectors and nucleic acids to make CAR-T and iPSC derivatives.
Guidance for CMC research and evaluation of immune cell therapy products 14 Provides the scope of immune cell therapy products.
Describes the detailed CMC technical requirements, including raw materials, manufacture, quality control, etc.
Clarifies the regulation of donor cell collection procedures. Illustrates the requirements for production capacity changes.

Nonclinical
Guidance for nonclinical research and evaluation of gene therapy products 15 Clarifies the basic principle of nonclinical study design and implement regarding gene therapy products.
Illustrates how to select proper animal model, the possibility to use of organoids instead of animal model, and the technical points to perform "proof-of-concept" study.
Guidance for nonclinical research and evaluation of gene-modified cellular products 16 Describes the study design of nonclinical research specifically to gene-edited cellular products, including vector-modified cellular products and CRISPR-Cas edited cellular products, etc.
Clarifies the technical requirements of tumorigenic/carcinogenic studies.

Clinical
Guidance for clinical trial research of immune cell products 17 Describes the study design of clinical research specifically to immune cell products.
Describes the toxicity and management of CAR-T products.
Guidance for long-term surveillance of gene therapy products 18 Describes the clinical study design in the follow-up of patients administered with gene therapy products Introduces the specific considerations of testing design for integrating vectors.
Guidance for clinical trial design of oncolytic virus-based products 19 Describes the clinical study design of oncolytic virus-based products, including administrative routes, dosing and clinical endpoint selection, etc.
Describes the design and analysis of shedding studies for oncolytic products.
Abbreviations: CMC, chemistry, manufacturing and control; CAR-T, chimeric antigen receptor-T cell; PSC, pluripotent stem cell.  Figure 2B). In addition, oncolytic virus products, in vivo gene therapy products, and other personalized treatment products, etc. have also been submitted and approved. Of the 271 ATMP IND reviews, 217 were approved and 54 were rejected. The reasons for rejection mainly include a lack of essential data, safety issues in the raw mate-rials, failure to properly perform safety testing such as replication-competent lentivirus test, and that incomparability between toxicological batches and clinical trial batches.

Product types, targets, and indications
Overall, the diversity of product types, targets, and indications is growing. From 2002 to 2016, most ATMPs submitted were oncolytic viruses and cell products without genetic manipulation procedures. Since 2017, as a rapid follow-up of approved CAR-T products in the world, various types of cellular products were submitted, such as CAR-T, TCR-T, TIL, CRISPR-Cas9-modified cell products. The types of ATMPs approved for IND have gradually diversified from 2019, when CAR-T products with multiantigen targeting, stem cell products and AAV products became popular ( Figure 3A). Among them CAR-T represented the largest number of ATMPs submitted. As of November 2022, 46 CD19 CAR-T INDs have been submitted in China. The number of novel types of CAR-T also increases, including universal CAR-T, fast-made CAR-T and nonviral vector-modified CAR-T products, etc. 20 In terms of the targets of CAR-T products, 79.2% of CAR-T products focused on two targets, CD19 and BCMA ( Figure 3B). Other targets of the minority of products include CD20, CD22 and solid tumor targets such as GPC3. In stem cell field, mesenchymal stem cell prod-ucts accounted for 88% of the stem cell products from 2004−2019. In 2021, this proportion has reduced to 76%. Notably, the majority of ATMP INDs from 2017 to November 2022 had repeated targets, similar cell types and indications ( Figure 3B,C). Oncology diseases are the main indication for all submitted ATMP INDs. Most CAR-T products were indicated to treat hematological cancers, while four solid tumor CAR-T products have been approved in clinical trial.
Seventy-three INDs of stem cell products have been submitted during 2004−2022, in which most are mesenchymal stem cells, with a few human pluripotent stem cell (hPSC)-derived products and adult stem cell products. The indications of stem cell products were highly diversified, which include skin and subcutaneous disorders, graft versus host diseases, neuromuscular diseases, digestive disorders, pulmonary fibrosis, among others. The majority of INDs of gene therapy products are AAV products during 2018−2022, and 13 AAV products have been approved in clinical trials, which mainly aims to treat hemophilia and ophthalmology diseases. Different serotypes of are used in these AAV products, including AAV2, AAV9 and other new serotypes. For tissue-engineered products, a number of products have been discussed in pre-IND meetings, including 3D-bioprinting blood vessels, human corneal endothelium and other types of tissue products, and some products are approved in clinical trials.

CHALLENGES AND PERSPECTIVES
Overall the regulatory reforms exerted profound influence on the innovation of cellular and gene therapy products in China. 21 While the data show that China's ATMP industry is lagging behind in terms of the innovative targets and the coverage of indications. The increase of ATMP application in treating serious diseases could provide more therapeutic strategy and contribute to meeting the unmet clinical need. Many ATMPs are translated from novel advances in stillmaturing fields of basic sciences, posing diverse challenges for development, including limited characterization, risk management in clinical trial and complex comparability study, such as individual donor tissue collection, multiple manufacturing sites, innovative device and materials, immune-deficient animal model, and limited clinical subjects. Meanwhile, the heterogeneity of ATMPs is obvious, which arises from the variability in donor tissues, manufacturing processes and analytical methods, etc. And, limited production capacity, expensive price, and other factors prevent ATMPs from large-scale production and widely commercial use. 22 From CMC perspective, phase-appropriate requirements for production of gene manipulation tools and other raw materials are important, while somehow difficult to articulate. Process changes inevitably happen in clinical trial and commercial stages, and the design and implementation of comparability study is crucial. Among all types of ATMPs, stem cell products are remarkably complex and varied in their manufacturing processes including methods for cell culture, induction of differentiation, cell storage and engraftment. 23,24 Generally it is difficult to assess whether prechange process and postchange process are analytically comparable, and nonclinical even clinical studies are needed in certain occasions. 25 Therefore, in-depth analysis and discussions are needed to share regulatory considerations on CMC, nonclinical and clinical experience of comparability assessments and ultimately achieve convergence. 26 From the pre-clinical aspect, there is no scientific consensus on rational animal models to test cellular products. Commonly, the challenges arise when we evaluate the potential tumorigenicity after cell product transplantation due to the difficulties in detecting the residual proliferative cells and the lack of proper animal models. 27 In terms of the clinical trial, the use of history study data (e.g. Investigator-Initiated Clinical Trial data) and endpoint selection strategy are difficult to justify. The outcomes of the clinical trials of ATMPs also bear uncertainty partly due to the disparities among patients. Therefore, it is challenging for the drug administrative agencies to perform the benefit-risk analysis and review the ATMPs, which may be controversial in terms of safety and efficacy. 28 Sound principles are required to regulate such types of complex products in a science-based and risk-based manner. For example, for the clinical use of genetically modified organisms, the environmental risk assessment is crucial in each application to prevent the potential harm to the environment and population. 29 Regarding the genetically engineered cellular products, attentions should be paid to safety risks such as insertional mutations and activation of oncogenes. Tumorigenic/carcinogenic research can be designed based on the risk assessment results, which is typically more important for hPSCderived products with higher risky of tumor formation. Traditionally AAV is considered as nonintegrative vectors, while sequencing data suggest the potential integration capability of AAV in certain cells, which may impact the safety of AAV products. 30 So, long-term surveillance is still necessary to monitor safety and efficacy in AAV clinical trials.
To meet the continuous increasing medical need and foster the development of ATMPs, it is prior to establish the regulatory framework of ATMPs and to safely accelerate clinical applications. 31 It is encouraged to use the expedited regulatory programs so as to make the review process more efficient for ATMPs, especially for those highly innovative products from small companies. And the agency will refashion the regulatory tools to establish a specific framework of ATMPs. In 2019, the National Drug Regulation Science Program of China has initiated and boosted the issuance of ATMP regulatory guidelines. According to the schedule, the Program will continuously support the high-quality regulation of stem cell therapies and gene therapies to accomplish more targets in the following years (https://www.nmpa.gov.cn/directory/ web/nmpa/yaowen/ypjgyw/20210628171415103.html). As a result, large numbers of technical guidelines were drafted and successfully issued in recent years. And, ATMPs of high-quality and better efficacy increase significantly. Scientific judgment and cross-discipline collaborations are encouraged to fulfill the true innovation and promote more ATMPs toward the process of market authorization in China. Consolidated efforts are required to strengthen the regulatory framework, including the update of guidelines, highly effective communications with stakeholders, fostering a partnership with international regulatory agencies to achieve convergence. [32][33][34]

A U T H O R C O N T R I B U T I O N S
J.L. analyzed the data and wrote the manuscript. L.X. collected the data and revised the manuscript. W.W. proposed the topic and revised the manuscript. W.H. conceived and revised the manuscript. All authors read and approved the final manuscript.

A C K N O W L E D G M E N T S
The authors gratefully acknowledge the nonclinical and clinical review team of ATMPs in CDE, NMPA for valuable discussions.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflict of interests.

F U N D I N G I N F O R M AT I O N
The authors received no specific funding for this work.

D ATA AVA I L A B I L I T Y S TAT E M E N T
The data analyzed can be found in the database of NMPA's Registration and Information Disclosure Platform for Drug (https://www.nmpa.gov.cn/yaopin/index.html) and Center for Drug Evaluation (CDE) (http://www.cde.org.cn/).